Viruses, especially retroviruses such as HIV, can become rapidly resistant to drugs used to treat the infection. This extreme adaptability of retroviruses is due to the high error rate of the reverse transcriptase enzyme responsible for transcribing its RNA genome. HIV is an example of such a hyper-mutable virus. It has diverged into two major species, HIV-1 and HIV-2, each of which has many clades, subtypes and drug resistant variations.
Strategies for coping with emergence of viral drug-resistant strains include combination drug therapies (Lange (1996) AIDS 10 Suppl 1:S27-S30). Drugs against different viral proteins and drugs against multiple sites on the same protein are commonly used as a strategy to overcome the adaptability of the virus. Combination therapies for retroviruses, using, e.g., protease inhibitors and nucleoside analogues, such as AZT, ddI, ddC and d4T, can become ineffectual; the virus develops complete resistance in a relatively short period of time (Birch (1998) AIDS 12:680-681; Roberts (1998) AIDS 12:453-460; Yang (1997) Leukemia 11 Suppl 3:89-92; Demeter (1997) J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 14(2):136-144; Kuritzkes (1996) AIDS 10 Suppl 5:S27-S31). Furthermore, no effective anti-retroviral vaccine is currently available (Bolognesi (1998) Nature 391:638-639; Bangham (1997) Lancet 350:1617-1621).
The HIV-1 caused AIDS epidemic began about 18 years ago. Since then the number of new cases have increased over time. By the end of 1994, 1,025,073 AIDS cases had been reported to the WHO, with a 20% increase in the number of cases since December, 1993 (Galli (1995) Q. J. Nucl. Med. 39:147-155). By the year 2000, the WHO predicts that there will be 30 to 40 million cumulative HIV-1 infections in the world (Stoneburner (1994) Acta Paediatr. Suppl. 400:1-4). Thus, there exists a great need for compounds effective against retroviruses such as HIV-1. The present invention fulfills these and other needs.